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This includes previous work examining multi\u2010walled carbon nanotube (MWCNT)\u2010induced eosinophilic inflammation, in which a more exaggerated M2a phenotype was observed in female alveolar macrophages (AMs) compared to males. The mechanisms responsible for this sex difference in AM phenotype are still unclear, but estrogen receptor (ER) signaling is a likely contributor. Accordingly, male AMs downregulated ER\u03b1 expression after MWCNT exposure while female AMs did not. Thus, ER antagonist Fulvestrant was administered prior to MWCNT instillation. In females, Fulvestrant significantly attenuated MWCNT\u2010induced M2a gene expression and eosinophilia without affecting IL\u201033. In males, Fulvestrant did not affect eosinophil recruitment but reduced IL\u201033 and M2a genes compared to controls. Regulation of cholesterol efflux and oxysterol synthesis is a potential mechanism through which estrogen promotes the M2a phenotype. Levels of oxysterols 25\u2010OHC and 7\u03b1,25\u2010OHC were higher in the airways of MWCNT\u2010exposed males compared to MWCNT\u2010females, which corresponds with the lower IL\u20101\u03b2 production and greater macrophage recruitment previously observed in males. Sex\u2010based changes in cholesterol efflux transporters\n                    <jats:italic>Abca1<\/jats:italic>\n                    and\n                    <jats:italic>Abcg1<\/jats:italic>\n                    were also observed after MWCNT exposure with or without Fulvestrant. In\u00a0vitro culture with estrogen decreased cellular cholesterol and increased the M2a response in female AMs, but did not affect cholesterol content in male AMs and reduced M2a polarization. These results reveal the modulation of (oxy)sterols as a potential mechanism through which estrogen signaling may regulate AM phenotype resulting in sex differences in downstream respiratory inflammation.\n                  <\/jats:p>","DOI":"10.1096\/fj.202301571rr","type":"journal-article","created":{"date-parts":[[2023,12,10]],"date-time":"2023-12-10T06:43:46Z","timestamp":1702190626000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Estrogen contributes to sex differences in M2a macrophages during multi\u2010walled carbon nanotube\u2010induced respiratory inflammation"],"prefix":"10.1096","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5387-9026","authenticated-orcid":false,"given":"Jessica L.","family":"Ray","sequence":"first","affiliation":[{"name":"Center for Environmental Health Sciences University of Montana  Missoula Montana 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